Dataset Information

Patisiran for the Treatment of Transthyretin-mediated Amyloidosis with Cardiomyopathy.

ABSTRACT: Transthyretin (TTR) is a tetrameric protein, synthesized primarily by the liver, that acts as a physiological transport protein for retinol and thyroxine. TTR can misfold into pathogenic amyloid fibrils that deposit in the heart and nerves, causing a life-threatening transthyretin amyloidosis cardiomyopathy (ATTR-CM), and a progressive and debilitating polyneuropathy (ATTR-PN). Recent therapeutic advances have resulted in the development of drugs that reduce TTR production. Patisiran is a small interfering RNA that disrupts the complimentary mRNA and inhibits TTR synthesis, and is the first gene-silencing medication licensed for the treatment of ATTR amyloidosis. After encouraging results following the use of patisiran for the treatment of patients with ATTR-PN, there has been increasing interest in the use of patisiran for the treatment of ATTR-CM. Various studies have demonstrated improvements across a wide range of cardiac biomarkers following treatment with patisiran, and have changed the perception of ATTR-CM from being thought of as a terminal disease process, to now being regarded as a treatable disease. These successes represent a huge milestone and have the potential to revolutionize the landscape of treatment for ATTR-CM. However, the long-term safety of patisiran and how best to monitor cardiac response to treatment remain to be determined.

SUBMITTER: Ioannou A

PROVIDER: S-EPMC10339464 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Patisiran for the Treatment of Transthyretin-mediated Amyloidosis with Cardiomyopathy.

Ioannou Adam A Fontana Marianna M Gillmore Julian D JD

Heart international 20230608 1

Transthyretin (TTR) is a tetrameric protein, synthesized primarily by the liver, that acts as a physiological transport protein for retinol and thyroxine. TTR can misfold into pathogenic amyloid fibrils that deposit in the heart and nerves, causing a life-threatening transthyretin amyloidosis cardiomyopathy (ATTR-CM), and a progressive and debilitating polyneuropathy (ATTR-PN). Recent therapeutic advances have resulted in the development of drugs that reduce TTR production. Patisiran is a small ...[more]

PMID: 37456349

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Project description:BackgroundPatisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18 months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. In this 24-month Phase II open-label extension study, we evaluated the effects of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on safety, serum transthyretin levels, and clinical parameters. Efficacy assessments included modified Neuropathy Impairment Score +7 (mNIS+7) and multiple disease-relevant measures. Cardiac assessments were performed in a pre-specified cardiac subgroup.ResultsTwenty-seven patients entered this study, including 12 (44%) with ambulation difficulties due to their neuropathy and 11 (41%) who met criteria for the cardiac subgroup. During treatment, the majority of adverse events were mild/moderate in severity; there were no drug-related adverse events leading to treatment discontinuation. The most common drug-related adverse events were flushing and infusion-related reactions (22% each). Patisiran resulted in rapid, robust (~ 82%), and sustained reduction of mean transthyretin levels over 24 months. A mean 6.95-point decrease (improvement) in mNIS+7 from baseline was observed at 24 months. Patisiran's impact on mNIS+7 was irrespective of concomitant tafamidis or diflunisal use, sex, or age. Clinical assessments of motor function, autonomic symptoms, disease stage, and quality of life remained stable over 24 months. No significant changes were observed for echocardiographic measures or cardiac biomarkers in the cardiac subgroup. Exploratory analyses demonstrated improvements in nerve-fiber density with corresponding reductions in amyloid burden observed in skin biopsies over 24 months.ConclusionsLong-term treatment with patisiran had an acceptable safety profile and was associated with halting/improvement of polyneuropathy progression in patients with hATTR amyloidosis.Trial registrationThe study was registered at ClinicalTrials.gov (identifier: NCT01961921 ) on October 14, 2013.

Dataset Information

Patisiran for the Treatment of Transthyretin-mediated Amyloidosis with Cardiomyopathy.

Publications

Patisiran for the Treatment of Transthyretin-mediated Amyloidosis with Cardiomyopathy.

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